| text | The complement component 5a receptor 1 (C5AR1; also known as CD88) is a G protein-coupled receptor expressed on myeloid cells such as neutrophils and monocytes, as well as on non-immune epithelial cells (van Werkhoven MB et al., 2013; Nürg B et al., 2021). C5AR1 is activated by C5a, an anaphylatoxin generated through proteolytic cleavage of complement component C5. The C5a:C5AR1 interaction triggers degranulation of mast cell, leading to histamine release, and promotes a robust chemoattractant signal for leukocytes (Gerard NP and Gerard C, 1991; Guo RF & Ward PA 2005; Feng Y et al., 2023). Overactivation of C5a:C5AR1 signaling has been implicated in pathological inflammation and tissue injury in conditions such as septic shock and viral infections, including severe COVID‑19 (Carvelli J et al., 2020; Bauer M et al., 2021; reviewed by Cedzyński M et al., 2019; Wang SSY et al., 2024). C5AR1 antagonists act by competitively blocking the receptor, thereby preventing C5a-driven pro-inflammatory responses, including chemotaxis, oxidative burst, and integrin upregulation (Bekker P et al., 2016; Li XX et al., 2020; Cyranka L et al., 2023; Schartz ND et al., 2024). Among these, avacopan is an orally active small-molecule C5AR1 inhibitor (also known as CCX168) approved as a glucocorticoid-sparing therapy in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, specifically severe active granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) (Jayne DRW et al., 2021, Harigai M & Takada H, 2022; Li A, 2022; Gabilan C et al., 2022; Cortazar FB et al., 2023; Nguyen ID et al., 2023). Similarly, avdoralimab (IPH5401), a fully human IgG kappa monoclonal antibody targeting C5AR1, has shown promising immunomodulatory effects in clinical trials by inhibiting C5a-induced activation of neutrophils and subsets of myeloid-derived suppressor cells (MDSCs). Avdoralimab continues to be evaluated in complement-associated inflammation and oncology settings (Carvelli J et al., 2020, 2022; Passeron T et al., 2024). |
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